tbuckley/cabot-search huggingface dataset:
Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial
Authors: Andrés Elía, Leo Saldain, Silvia I. Vanzulli, Luisa A. Helguero, Caroline A. Lamb, Victoria Fabris, Gabriela Pataccini, Paula Martínez-Vazquez, Javier Burruchaga, Ines Caillet-Bois, Eunice Spengler, Gabriela Acosta Haab, Marcos Liguori, Alejandra Castets, Silvia Lovisi, María F. Abascal, Virginia Novaro, Jana Sánchez, Javier Muñoz, José M. Belizán, Martín C. Abba, Hugo Gass, Paola Rojas, Claudia Lanari
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844). Patients and Methods: Twenty patients with luminal breast carcinomas with PRA/PRB &amp;gt; 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment. Results: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling. Conclusions: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833
Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study
Authors: Ismael Fernández-Miranda, Lucía Pedrosa, Marta Llanos, Fernando F. Franco, Sagrario Gómez, Paloma Martín-Acosta, Francisco R. García-Arroyo, Josep Gumá, Beatriz Horcajo, Ana K. Ballesteros, Laura Gálvez, Natividad Martínez, Miguel Marín, Silvia Sequero, Marta Navarro, Natalia Yanguas-Casás, Virginia Calvo, Antonio Rueda-Domínguez, Mariano Provencio, Margarita Sánchez-Beato
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. Experimental Design: We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. Results: Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P &amp;lt; 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. Conclusions: Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.
Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas
Authors: Mirela-Diana Ilie, Alexandre Vasiljevic, Philippe Bertolino, Gérald Raverot
Journal: Endocrine Reviews (2022)

Pituitary adenomas (PAs) are neoplasms derived from the endocrine cells of the anterior pituitary gland. Most frequently, they are benign tumors, but may sometimes display an aggressive course, and in some cases metastasize. Their biology, including their wide range of behavior, is only partly understood. In terms of therapeutic targeting, most PAs are easily treated with available medical treatments, surgery, and sometimes radiotherapy. Nevertheless, gonadotroph adenomas lack medical therapeutic options, and treatment of aggressive PAs and pituitary carcinomas remains challenging. Here, we present an overview of the implications of the tumor microenvironment in PAs, reviewing its composition and function, as well as published cases that have been treated thus far using tumor microenvironment-targeting therapies. Additionally, we discuss emerging views, such as the concept of nonangiogenic tumors, and present perspectives regarding treatments that may represent future potential therapeutic options. Tumor-infiltrating lymphocytes, tumor-associated macrophages, folliculostellate cells, tumor-associated fibroblasts, angiogenesis, as well as the extracellular matrix and its remodeling, all have complex roles in the biology of PAs. They have been linked to hormone production/secretion, size, invasion, proliferation, progression/recurrence, and treatment response in PAs. From a therapeutic perspective, immune-checkpoint inhibitors and bevacizumab have already shown a degree of efficacy in aggressive PAs and pituitary carcinomas, and the use of numerous other tumor microenvironment-targeting therapies can be foreseen. In conclusion, similar to other cancers, understanding the tumor microenvironment improves our understanding of PA biology beyond genetics and epigenetics, and constitutes an important tool for developing future therapies.
α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo
Authors: Yan Shi, Candy Lee, Peng Sang, Zaid Amso, David Huang, Weixia Zhong, Meng Gu, Lulu Wei, Vân T.B. Nguyen-Tran, Jingyao Zhang, Weijun Shen, Jianfeng Cai
Journal: Acta Pharmaceutica Sinica B (2022)

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t1/2 > 14 days) compared to t1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.
Human Leukocyte Antigen Alleles Associated with Interstitial Lung Disease in North Americans with Idiopathic Inflammatory Myopathy
Authors: Cheilonda Johnson, Adam I. Schiffenbauer, Frederick W. Miller, Jamie Perin, Sonye K. Danoff, Avantika R. Diwadkar, Jaehyun Joo, Blanca E. Himes, Nuala J. Meyer, Lisa G. Rider, Terrance P. O’Hanlon, Willy A. Flegel, Sharon D. Adams, Iago Pinal Fernandez, Mehmet Tevfik Dorak, Julie J. Paik, Jemima Albayda, Eleni Tiniakou, Lisa Christopher-Stine, Andrew L. Mammen
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Human Leukocyte Antigen Alleles Associated with Interstitial Lung Disease in North Americans with Idiopathic Inflammatory Myopathy." American Journal of Respiratory and Critical Care Medicine, 207(5), pp. 619–622
N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells
Authors: Zhihua Liu, Nanxin Zheng, Juan Li, Chao Li, Dan Zheng, Xue Jiang, Xiaoying Ge, Min Liu, Lianjie Liu, Zhen Song, Leilei Bao, Yangyang Zhan, Xianhua Gao
Journal: Drug Resistance Updates (2022)
Transcriptome-based Phylogeny of the Semi-aquatic Bugs (Hemiptera: Heteroptera: Gerromorpha) Reveals Patterns of Lineage Expansion in a Series of New Adaptive Zones
Authors: David Armisén, Séverine Viala, Isabelle da Rocha Silva Cordeiro, Antonin Jean Johan Crumière, Elisa Hendaoui, Augustin Le Bouquin, Wandrille Duchemin, Emilia Santos, William Toubiana, Aidamalia Vargas-Lowman, Carla Fernanda Burguez Floriano, Dan A Polhemus, Yan-hui Wang, Locke Rowe, Felipe Ferraz Figueiredo Moreira, Abderrahman Khila
Journal: Molecular Biology and Evolution (2022)

Abstract Key innovations enable access to new adaptive zones and are often linked to increased species diversification. As such, innovations have attracted much attention, yet their concrete consequences on the subsequent evolutionary trajectory and diversification of the bearing lineages remain unclear. Water striders and relatives (Hemiptera: Heteroptera: Gerromorpha) represent a monophyletic lineage of insects that transitioned to live on the water–air interface and that diversified to occupy ponds, puddles, streams, mangroves and even oceans. This lineage offers an excellent model to study the patterns and processes underlying species diversification following the conquest of new adaptive zones. However, such studies require a reliable and comprehensive phylogeny of the infraorder. Based on whole transcriptomic datasets of 97 species and fossil records, we reconstructed a new phylogeny of the Gerromorpha that resolved inconsistencies and uncovered strong support for previously unknown relationships between some important taxa. We then used this phylogeny to reconstruct the ancestral state of a set of adaptations associated with water surface invasion (fluid locomotion, dispersal and transition to saline waters) and sexual dimorphism. Our results uncovered important patterns and dynamics of phenotypic evolution, revealing how the initial event of water surface invasion enabled multiple subsequent transitions to new adaptive zones on the water surfaces. This phylogeny and the associated transcriptomic datasets constitute highly valuable resources, making Gerromorpha an attractive model lineage to study phenotypic evolution.
Positron Emission Tomography–Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance)
Authors: Ann S. LaCasce, Travis Dockter, Amy S. Ruppert, Lale Kostakoglu, Heiko Schöder, Eric Hsi, Jeffrey Bogart, Bruce Cheson, Nina Wagner-Johnston, Jeremy Abramson, Kristie Blum, John P. Leonard, Nancy L. Bartlett
Journal: Journal of Clinical Oncology (2022)

Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)-adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET-) disease and intensifying treatment in patients with PET-positive (PET+) disease.
Preparing for the End Game
Authors: William T. Beck
Journal: Journal of Clinical Oncology (2022)

Recently, Jordan, a dear friend who had stage 4 lung cancer, died of his disease, a year and a half from his diagnosis.His tumor had activating mutations in the epidermal growth factor receptor, making him a candidate for treatment with osimertinib, a targeted therapy, one of the recent rewards of the remarkable advances in precision medicine.Jordan was my age, late 70s when he died.He was a lifetime nonsmoker, had several outstanding lung cancer oncologists, and was determined to fight his disease.That said, 3-year and 5-year survival rates for people with his disease are not high, but living beyond those years is statistically and biologically possible.That was not so in Jordan's case.
New Insights into the Pathogenesis of Mastocytosis: Emerging Concepts in Diagnosis and Therapy
Authors: Peter Valent, Cem Akin, Wolfgang R. Sperr, Hans-Peter Horny, Michel Arock, Dean D. Metcalfe, Stephen J. Galli
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of KIT. The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.
Over-the-scope clip and self-expandable metal stent: a comprehensive treatment for failed peroral endoscopic myotomy and fibrosis complications in idiopathic achalasia
Authors: Valeria D’Ovidio, Alessandra Cesarini, Daniele Lisi, Danilo Badiali, Marco E. Bazuro
Journal: Endoscopy (2022)

Achalasia is a rare esophageal motility disorder that affects both sexes and all ages. Peroral endoscopic myotomy (POEM) has been reported as an optional treatment since 2010 [1].
Introduction to the Theme “Development of New Drugs: Moving from the Bench to Bedside and Improved Patient Care”
Authors: Terrence F. Blaschke, Paul A. Insel, Susan G. Amara, Urs A. Meyer
Journal: The Annual Review of Pharmacology and Toxicology (2022)

Investigations in pharmacology and toxicology range from molecular studies to clinical care. Studies in basic and clinical pharmacology and in preclinical and clinical toxicology are all essential in bringing new knowledge and new drugs into clinical use. The 30 reviews in Volume 63 of the Annual Review of Pharmacology and Toxicology explore topics across this spectrum. Examples include "Zebrafish as a Mainstream Model for In Vivo Systems Pharmacology and Toxicology" and "Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond." Other reviews discuss components important for drug discovery and development and the use of pharmaceuticals in a variety of diseases. Air pollution continues to increase globally; accordingly, "Air Pollution-Related Neurotoxicity Across the Life Span" is a timely and forward-thinking review. Volume 63 also explores the use of contemporary technologies such as electronic health records, pharmacogenetics, and new drug delivery systems that help enhance and improve the utility of new therapies.
Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease
Authors: Xiaoqin Wu, Xiude Fan, Tatsunori Miyata, Adam Kim, Christina K. Cajigas-Du Ross, Semanti Ray, Emily Huang, Moyinoluwa Taiwo, Rakesh Arya, Jianguo Wu, Laura E. Nagy
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.
After the Storm: Regeneration, Repair, and Reestablishment of Homeostasis Between the Alveolar Epithelium and Innate Immune System Following Viral Lung Injury
Authors: Joseph D. Planer, Edward E. Morrisey
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

The mammalian lung has an enormous environmental-epithelial interface that is optimized to accomplish the principal function of the respiratory system, gas exchange. One consequence of evolving such a large surface area is that the lung epithelium is continuously exposed to toxins, irritants, and pathogens. Maintaining homeostasis in this environment requires a delicate balance of cellular signaling between the epithelium and innate immune system. Following injury, the epithelium can be either fully regenerated in form and function or repaired by forming dysplastic scar tissue. In this review, we describe the major mechanisms of damage, regeneration, and repair within the alveolar niche where gas exchange occurs. With a focus on viral infection, we summarize recent work that has established how epithelial proliferation is arrested during infection and how the innate immune system guides its reconstitution during recovery. The consequences of these processes going awry are also considered, with an emphasis on how this will impact postpandemic pulmonary biology and medicine.
The Pathology of Asthma: What Is Obstructing Our View?
Authors: Helena Aegerter, Bart N. Lambrecht
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Despite the advent of sophisticated and efficient new biologics to treat inflammation in asthma, the disease persists. Even following treatment, many patients still experience the well-known symptoms of wheezing, shortness of breath, and coughing. What are we missing? Here we examine the evidence that mucus plugs contribute to a substantial portion of disease, not only by physically obstructing the airways but also by perpetuating inflammation. In this way, mucus plugs may act as an immunogenic stimulus even in the absence of allergen or with the use of current therapeutics. The alterations of several parameters of mucus biology, driven by type 2 inflammation, result in sticky and tenacious sputum, which represents a potent threat, first due to the difficulties in expectoration and second by acting as a platform for viral, bacterial, or fungal colonization that allows exacerbations. Therefore, in this way, mucus plugs are an overlooked but critical feature of asthmatic airway disease.
Silencing EGFR-upregulated expression of CD55 and CD59 activates the complement system and sensitizes lung cancer to checkpoint blockade
Authors: Fei Shao, Yibo Gao, Wei Wang, Haiyan He, Liwei Xiao, Xiao Geng, Yan Xia, Dong Guo, Jing Fang, Jie He, Zhimin Lu
Journal: Nature Cancer (2022)
A digital physician peer to automatically detect erroneous prescriptions in radiotherapy
Authors: Qiongge Li, Jean Wright, Russell Hales, Ranh Voong, Todd McNutt
Journal: npj Digital Medicine (2022)

Appropriate dosing of radiation is crucial to patient safety in radiotherapy. Current quality assurance depends heavily on a physician peer-review process, which includes a review of the treatment plan's dose and fractionation. Potentially, physicians may not identify errors during this manual peer review due to time constraints and caseload. A novel prescription anomaly detection algorithm is designed that utilizes historical data from the past to predict anomalous cases. Such a tool can serve as an electronic peer who will assist the peer-review process providing extra safety to the patients. In our primary model, we create two dissimilarity metrics, R and F. R defining how far a new patient's prescription is from historical prescriptions. F represents how far away a patient's feature set is from that of the group with an identical or similar prescription. We flag prescription if either metric is greater than specific optimized cut-off values. We use thoracic cancer patients (n = 2504) as an example and extracted seven features. Our testing set f1 score is between 73%-94% for different treatment technique groups. We also independently validate our results by conducting a mock peer review with three thoracic specialists. Our model has a lower type II error rate compared to the manual peer-review by physicians.
Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials
Authors: Ting Martin Ma, Yilun Sun, Shawn Malone, Mack Roach, David Dearnaley, Thomas M. Pisansky, Felix Y. Feng, Howard M. Sandler, Jason A. Efstathiou, Isabel Syndikus, Emma C. Hall, Alison C. Tree, Matthew R. Sydes, Claire Cruickshank, Soumyajit Roy, Michel Bolla, Philippe Maingon, Theo De Reijke, Abdenour Nabid, Nathalie Carrier, Luis Souhami, Almudena Zapatero, Araceli Guerrero, Ana Alvarez, Carmen Gonzalez San-Segundo, Xavier Maldonado, Tahmineh Romero, Michael L. Steinberg, Luca F. Valle, Matthew B. Rettig, Nicholas G. Nickols, Jonathan E. Shoag, Robert E. Reiter, Nicholas G. Zaorsky, Angela Y. Jia, Jorge A. Garcia, Daniel E. Spratt, Amar U. Kishan
Journal: Journal of Clinical Oncology (2022)

The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT).
Incorporating Information From Proxies for Patient-Centered Outcomes in Adult and Pediatric Oncology Settings
Authors: Jessica Roydhouse, Bryce B. Reeve
Journal: Journal of Clinical Oncology (2022)

benefit from careful consideration.Without adequate evidence, these complex decisions will be ad hoc, uninformed, and unstandardized.Research to better inform these decisions is important and may ultimately lead to improvements in patient-centered research and care in oncology.In the interim, current studies can help build the evidence base to inform future standards by documenting the reason for proxy use and collecting more information about proxies, including information about what may help proxies improve their reports and thus the quality of a source of data about patients.